17-78113183-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001127198.5(TMC6):c.2383C>T(p.Pro795Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000385 in 1,558,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P795L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: TMC6 NM_001127198.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.508

Genes affected

TMC6 (HGNC:18021): (transmembrane channel like 6) Epidermodysplasia verruciformis (EV) is an autosomal recessive dermatosis characterized by abnormal susceptibility to human papillomaviruses (HPVs) and a high rate of progression to squamous cell carcinoma on sun-exposed skin. EV is caused by mutations in either of two adjacent genes located on chromosome 17q25.3. Both of these genes encode integral membrane proteins that localize to the endoplasmic reticulum and are predicted to form transmembrane channels. This gene encodes a transmembrane channel-like protein with 10 transmembrane domains and 2 leucine zipper motifs. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.102149665).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC6	NM_001127198.5	c.2383C>T	p.Pro795Ser	missense_variant	20/20	ENST00000590602.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC6	ENST00000590602.6	c.2383C>T	p.Pro795Ser	missense_variant	20/20	2	NM_001127198.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000356 AC: 5 AN: 1406056 Hom.: 0 Cov.: 31 AF XY: 0.00000432 AC XY: 3 AN XY: 694084

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000462

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74362

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000880 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epidermodysplasia verruciformis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 659016). This variant has not been reported in the literature in individuals affected with TMC6-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 795 of the TMC6 protein (p.Pro795Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	3.9
Dann	Uncertain	0.99
DEOGEN2	Benign	0.025	T;T;T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.14	N
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.10	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L;L;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.32	T
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.010	B;B;B;B;B
Vest4		0.098
MutPred		0.36		Gain of phosphorylation at P795 (P = 0.0222);Gain of phosphorylation at P795 (P = 0.0222);Gain of phosphorylation at P795 (P = 0.0222);.;.;
MVP		0.41
MPC		0.16
ClinPred		0.078	T
GERP RS		-0.72
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.13
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs755596766; hg19: chr17-76109264;